Metastasis is responsible for most cancer deaths, including breast, lung or head and neck cancers. However, the molecular processes underlying cellular changes that promote tumor metastasis are still poorly understood. We found that p90 Ribosomal S6 kinase 2 (RSK2) is commonly important to promote multiple steps that comprise tumor metastasis, such as resistance to anoikis induction, cell migration and invasion, and tumor metastasis in metastatic human cancers including breast, lung, and head and neck cancers. Through incorporated phosphor-proteomics and genomics based studies, we demonstrated that RSK2 mediates anti-anoikis, pro-invasive and pro-metastatic signals by phosphorylating a spectrum of downstream factors. In particular, we identified novel substrates of RSK2, including apoptosis signal-regulating kinase 1 (ASK1) and IRS1, to provide anti-anoikis protection and promote pro-invasive and pro-metastatic potentials in cancer cells, respectively. Moreover, we demonstrated that RSK2-CREB signaling pathway regulate gene expression of a group of proteins that are involved in cell death regulation including pro-apoptotic ING3 to provide anti-anoikis protection, as well as proteins that promote epithelial-mesenchymal transition (EMT) including vitronectin (VTN). These factors intertwine with each other to form a signaling network, which mediates RSK2 signals to provide a pro-survival and pro-metastatic advantage to human cancers in both transcription-dependent and -independent manners. Furthermore, our preliminary studies showed that treatment with a novel, bio-available RSK specific inhibitor, FMK-MEA significantly attenuates cancer cell invasion and tumor metastasis. Thus, our central hypothesis is that RSK2 signaling pathway is commonly activated in metastatic cancers, which provides anti-anoikis protection and promotes cancer cell invasion and tumor metastasis in both transcription-dependent and -independent manners. RSK2 signaling represents an attractive anti-metastasis therapy in cancer treatment. Three Specific Aims are proposed: (1) To determine whether RSK2 provides anti-anoikis protection to cancer cells by inhibiting a newly identified phosphorylation target ASK1 and downregulating CREB-dependent gene expression of pro-apoptotic protein ING3; (2) To determine whether RSK2 mediates pro-invasive and pro-migratory signals in cancer cells by phosphorylating pro-metastatic protein IRS1 and upregulating gene expression of EMT promoting effector VTN that is a RSK2-CREB transcription target; (3) To validate RSK2 and its signaling effectors in tumor specimens as therapeutic targets and treat human metastatic cancers in vitro and in vivo using a novel RSK inhibitor FMK-MEA in combination with anti-cancer agents including cisplatin.